These experiments will examine the properties of excitatory amino acid receptors on motor neurons and the way in which glutamate can regulate [Ca2+]i in these cells. These studies are aimed at examining the possibility that glutamate mediated "excitotoxicity" may be responsible for the degeneration of motor neurons in ALS and related disorders. Several types of investigations are proposed. The electrophysiological effects of glutamate and selective glutamate receptor agonists will be examined in thin slices of the spinal cord using patch-clamp techniques. These recordings will be accompanied by simultaneous measurements of [Ca2+]i in these preparations. We shall carry out similar studies using preparations from the motor neuron degeneration (Mnd) mouse and animals infected with Theiler's murine encephalomyelitis virus (TMEV), two animal models of ALS. It is anticipated that the results of these experiments should provide important information about the physiology of motor neurons and may suggest the existence of alterations in Ca2+ regulatory mechanisms in these cells that could underlie their degeneration in ALS and related disorders.